16-substituted androstanes and androstenes



United States Patent 3,163,641 16-SUBSTITUTED ANDRQSTANES ANDANDRQSTENES Robert G. Christiansen, Schodaclr, Raymond 0. Clinton, EastGreenbush, and John W. Dean, Sand Lake, N.Y.,

assignors to Sterling Drug Ina, New York, N.Y., a

corporation of Delaware No Drawing. Filed Nov. 15, 1962, Ser. No.2381329 19 Claims. (Cl. 260239.5)

This invention relates to new steroid compounds of the androstane andandrostene series substituted in the 16- position, and to processes forpreparing them.

A particular aspect of the invention is concerned with compoundsselected from the group consisting of O CH3 1 OHR I V p y p: T0124; 0: J

I and Y wherein Risa member of the group consisting of pyridyl,.

thienyl, furyl, phenylvinyl and phenyl substituted by from one to threesubstituents selected from halogen (including fluorine, chlorine,bromine or iodine), di-loweralkylamino, lower-alkoxy and benzyloxy; R isaniember of the group consisting-ofJhydrogen and .A cyl'; and X is amember of the'gr oup consisting of O, (H) (OH) and v(H)(OAcyl); Acyl ineach instance being a carboxylic acid acyl group having from one to tencarbon atoms and a molecular weightless than 200; and acid-addition andv quaternary ammonium salts of basic members thereof.

In the above Formulas I, II and III, R, when pyridyl,

, thienyl or furyl can have any of the possible. orientations,

that is, 2-pyridyl, 3-pyridyl, 4-pyridyl, Z-thienyl, B-thienyl, Z-furylor S-furyl. When R stands for phenyl substituted I bydi-loWer-alkylamino or lower-alkorry, thealkyl moieties can have fromone to about four carbon atoms.

When acyloxy radicals are present in the steroid mol'ecule, the acylradicals are preferably derived from carboxylic acids having from one toabout ten carbon'atoms,

' conventionally employed in the steroid art, and having 3,163,641Patented Dec. 29, 1964 ICC , [X is (H) (OH)] are prepared by condensingS-androsten- 3,8-o1-17-one or androstan-3B-ol-l7-one with theappropriate aldehyde, O CH-R, in the presence of a strong base. Thestrong base can be an alkali metal hydroxide,

lower-alkoxide, amide or the like, and the reaction takes place in aninert solvent at a temperature between about 50 C, and C.

Compounds of Formula IIv can be prepared from compounds of Formula I'bythe Oppenauer oxidation procedure. Compounds of Formula HI where X is Ocan be prepared from the compounds of Formula 111 when X is (H) (OH) bythe Oppenauer procedure or by chromic acid oxidation. The compounds ofFormula I where R is Acyl and of Formula IH when X is (H) (OAcyl) can beprepared from the corresponding carbinols by conventional esterificationprocedures. 7

Another particular aspect of the invention is concerned with compoundshaving the formula XI 3 II Where R" is a member of the group consistingof pyridyl, thienyl, furyl, l-lower-alkylpiperidyl, 4-oxocyclohexyl,4-oxirm'nocyclohexyl, 4-azacycloheptyl, 4-aza-5 oxocycloheptyl, andphenyl substituted by from one to three substituents selected fromhalogen (including fluorine,

chlorine, bromine and iodine), di-loweralkylamino and lower-alkoxy; andX: andX are members of the .group consisting of O, (H) (OH) and (H)(OAcyl), Acyl being a carboXylic acyl group having from one to tencarbon atoms and a molecular Weight less than about 200; and

acid-addition and quaternary ammonium saltsof basic ,members thereof.

In the above Formula IV,'R, when pyridyl, thienyl, furyl or l-loweralkylpiperidyl can have any of the possibleorientations, that is,Z-pyridyl, 3-pyridyl, l-pyridyl, Z-thienyl, 3v-thienyl, Z-furyl,3-furyl, l-lower-alkyl-Z- pipe'ridyl, 1-loWer-alkyl-3-piperidyl, orl-lower-alkyl 4-piperidyl. .When R" stands for l-lo'wer alkylpiperidyl,

or phenyl substituted by di-lower-alkylamino or loweralkoxy, the alkylmoieties can have from one to about 7 four' carbon atoms.

When X and X in Formula 1V represent (H) (OAcyl),'

the Acyl has the same meaning given hereinabove for compounds ofFormulas I, II and III.

The compounds ofFormula IV where R" ispyridyl, thienylffuryl, orphenyl'substituted by halogen, diloweralkylamino' orloWer-alkoXy-are'prepared by catalytically cycloalkyl-loWer-alkanoylreducing compounds of Formula III. A preferred proce dure comprisescatalytic hydrogenation at moderate pressure in the presence of apalladium catalyst supported on strontium carbonate. In some instancesthe 17-oxo group is also reduced to a 17;3-hydroxy group [X': (H)(01-1)].

The compounds of Formula N where R" is l-loweralkylpiperidyl areprepared by catalytic reduction of lower-alkyl quaternary ammonium saltsof compounds of Formula IV where R" is pyridyl.

The compounds of Formula IV where R" is 4-oxocyclohexyl,4-oximinocyclohexyl, 4-aza-5-oxocycloheptyl or 4-azacycloheptyl areprepared by a sequence of transformations as depicted by the followingfiow sheet using partial formulas showing Ring D of the steroid moietyonly:

In the foregoing formulas, R stands for hydrogen or Acyl as definedhereinabove. The compounds where R is hydrogen can be esterified, oroxidized to an oxo group, by conventional procedures at different stagesin the synthesis.

The 16 8-p-methoxybenzyl compound (V) is subjected to a reduction usinglithium in liquid ammonia. The resulting intermediate enol ether neednot be isolated but is hydrolyzed with oxalic acid and catalyticallyreduced to give the 16,8-(4-oxocyclohexylmethyl) compound (VI).

The latter is converted to its oxime (VII) by heating it withhydroxylamine hydrochloride in pyridine and ethanol. Beckmannrearrangement of the oxime (VII) to the16p-(4-aza-5-oxocycloheptylmethyl) c o m p o u n d (VIII) is effected bytreating the former with thionyl chloride in dioxane, The final stepcomprises reduction of the lactam (VIlI) to the16,8-(4-azacycloheptylmethyl) vascular properties.

calculated for the assigned structures.

compound (IX) with lithium aluminum hydride in tetrahydrofuran.

Those compounds of the invention which are basic in nature, that is,those of Formulas I-IV wherein R (or R") is pyridyl,l-lower-alkylpiperidyl, or phenyl substituted by di-lower-alkylamino,and of Formula 1X, readily form acid-addition salts upon addition ofstrong acids; and the tertiary amines of Formulas I-IV, wherein R (orR") is pyridyl, l-lower-alklylpiperidyl, or phenyl substituted bydi-lower-alkylamino, readily form quaternary ammonium salts uponaddition of esters of strong acids.

The quaternary ammonium salts are prepared by causing the tertiary amineto react with an ester of a strong inorganic or organic sulfonic acid,said ester preferably having a molecular weight less than about 200. Aparticularly preferred class of esters, because of their readyavailability, are lower-alkyl, lower-alkenyl and monocarbocyclicaryl-lower-alkyl esters, for example, methyl iodide, ethyl iodide, ethylbromide, propyl bromide, butyl bromide, allyl bromide, methyl sulfate,methyl benzenesulfonate, methyl p-toluenesulfonate, benzyl chloride,o-chlorobenzyl chloride, and the like. The reaction of the tertiaryamine and the quaternizing agent takes place upon simple admixture ofthe components, preferably in the presence of an inert organic solvent,although heating may be applied to accelerate the reaction.

The acid-addition and quaternary ammonium salts prefenably have anionswhich are pharmacologically acceptable, that is, the anions do notappreciably increase the toxicity of the compound as a whole towardanimal organisms. Such anions include, for example, the chloride,bromide, iodide, sulfate or acid sulfate, methanesulfonate,benzenesulfonate, and the like. Salts having toxic anions are, however,useful in that they serve as characterizing derivatives of the basicsteroids and serve as intermediates for non-toxic quaternary salts bycon veutional ion exchange reactions. All acid-addition salts,regardless of the nature of the anions, are useful as intermediates inthe purification of the free bases.

Endocrinological and pharmacological studies of the compounds of theinvention have shown that they possess useful metabolic, hormonal,anti-hormonal or cardio- In particular, they exhibit one or more of thefollowing activities: anabolic, androgenic, pituitary inhibiting,coronary dilator and antihypertensive.

The compounds of the invention can be prepared for use by dispersingthem in an aqueous suspension or by dissolving them in apharmacologically acceptable oil or oil-water emulsion for parenteraladministration; or by incorporation in tablet form with excipients fororal administration.

The structures of the compounds of the invention were established by themodes of synthesis, by ultraviolet and infrared spectral analysis, andby the fact that the values found upon elementary analysis correspondedto the Values The compounds of Formulas IV-IX were assigned thewit-configuration from the fact that catalytic reduction of l6-exodouble bonds is known to produce substituents having that orientation.

The following examples will further illustrate the invention without thelatter being limited thereby.

16-arylidene derivatives (I and III) of 5-andr0sten-3fi- 01-17-0112 andof androstan-3fl-ol-17-one.-These compounds were prepared by allowingthe steroidal ketone to react with a moderate excess (25-75%) of theappropriate aldehyde plus an equivalent quantity of'potassium hydroxide,all in solution in refluxing methanol. Often the condensation productcrystallized directly from the reaction solution after a short period atreflux; when it did not, heating was discontinued after an hour and thesolution was concentrated by distillation at reduced pressure. If thelatter procedure did not induce crystallization of the product, thereaction solution was diluted with water and the crude product thusprecipitated was collected by filtration. Recrystallization fromappropriate solvents (see Tables 1 and 2) afforded the pure compounds,for which .the data recorded in the tables wereS-androsten-Sfi-ol-17-one, 1

'6 3 furylniethylene) 5-andro- 'sten-3B-ol-17-one, 16-(4-fiuorobenzylidene) 5-androste'n- 3 ,8-0l-17-one, 16-(4-bromobenzylide11e) 5-androsten-3 13-01- determined. 1f7-one,16-(4-iodobenzylidene)5-androsten-3fi-ol-17-one,

, TABLE 1 16-Arylidene Derivatives (I) of 5-Andr0sten-3/3-0l-17-0neRotation Ultraviolet Spec- Example lfi-Arylidene Substituent (yield)M.P. (corn) (recrystallization solvent) 1016 1513911) trum Mm.

1 2,4-Dichlorobenzylidene (83.0%) 200.8204.6 (ethyl acetate) 1'0. 22339111 (1152108)?) i 0 2 2-Pyridylmethylene (81.6%) 200.0203.8(acetone) 126. 0 263 um (12,200);

' p 272 11111 (12,900); 298 Inn (20000). 3 4-Methoxybenzylidene (92.6%)2220-2202 (acetone) 15. 6 23221321 1 (8,(400)160) I 0 my. 28, 44-Dimethylaminobenzylidene (58.7%) 279.8284.0 (chloroformethanol) +14. 1251 my. (9,600);

323 m (6,700), 385 u (31,400) 5 Cinnamylidene (75.7%) 207.6 211.2(ethanolmethanol) 1. 198. 2 235 m (6,100);

. 333 11114 (40,100). 6-, 2-Methoxybenzylidene (87.3%) l29,2-135.2(acetone) +31. 6 234 my (7,300);

289 m (13,500); I 1 331 m (11,800). 7 4-Ohlorobenzylidene (69.5%)219.4222.2 (tetlahydrolnran) 32. 2 225 my (8,100);

l I 231 m (7,300); 7 a 299 m (23,600). 8 3,4,5-Trimethoxybenzylidene(78.8%) 132.8136.2 (benzene-n-hexane) 17. 3 24321; (11510216) m 94-Pyridyhnethy1ene (86.5%) 26l.2265.4 (ethylacetate) 5l. 0 280 In,(23,500).

' 16 (2,4 dichlorobenzylidene)5-androsten-3fi-o1-17- one (Example 1),16-(4-methoxybenzylidene) 5 androsten-fifl-ol-U-one (Example 3) i and16-(4-dimethylaminobenzylidene) 5 androsten-3,8-ol-17 one (Example 4)were found to cause a significant drop in blood pressure whenadministered orally to renal hypertensive rats at a dose level of 50mg./kg.

16 (2,4 dichlorobenzyli'dene)5-androsten-3B-ol-l7- one (Example 1) wasfound to cause pituitary and uterine hypertrophy in mature female ratsat a dose level of 20 mg./kg. per day. i

16 '(2 pyridylmethylene)5-androsten-3fi-ol-17-one (Example 2) was foundto have a coronary dilator activity 200% that of papaverine wheninjected into the isolated rabbit heart at a dose level of 0.025 mg. perheart.

dehyde, therecan beobtained, respectively, 16-(2-thienylmethylene)5-androsten-3fl-ol-17-one, 16-(3-thienylmetl1- 16-ArylideneDerivatives (III) of Aridrostam acid, tartaric acid, citricacid,'qi1inic acid, benzenesulfonic 16-(2,4,6-trichlorobenzylidene) 5androsten-3fi-ol-l7- one, or16-(3-chloro-4methoxybenzylidene)5-androsten- 3,6-ol-17-0ne.

16 (4-rhethoxybenzylidene) 5. androsten-3fl-ol-17-one can be caused toreact with acetic anhydride, propionic anhydride, caproyl chloride,succinic anhydride, fi-cyclopentylpropionyl chloride, benzoyl chloride,p-nitrooen'zoyl chloride, 3,4,5-trimethoxybenzoy1 chloride, phenylacetylchloride, or cinnamoyl chloride, by heating in the presence of pyridine,to give, respectively,3fl-acetoxy-16-(4-methoxybenzylidene)5-androsten-17-one, 3Bpropionoxy-l6- (4-methoxybenzylidene)5-androsten-17-one, 3fi-caproyl-0xy-16-(4 methoxybenzylidene)5-androsten-17-one, 3B-(fl-carboxypropionoxy) 16 (4 methoxybenzylidene)- 5-androsten-17-one,3B-( 8 cyclopentylpropionoxy)-16-(4-met-hoxybenzylidene)5-androsten-17-one, 3/3-benzoyloxy-16-(4-methoxybenzylidene) 5 androsten-l7-one, 3B-(pnitrobenzoyloxy) 16(4-methoxybenzylidene)-5-androsten-17-one, 3 B- 3,4,S-trimethoxybenzoyloxy) 16-(4-methoxybenzylidene)5-androsten-17-one,3p phenylaceto xy- 16-(4-methoxybenzylidene)5-androsten-17-one, or3,8-cinnamoyloxy-16-(4 methoxybenzyliclene)5-androsten-17- one.

16-(4-dimethylaminobenzylidene 5 androsten-SB-ol- 17-one can be causedto react with hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, lactic phenylethyl bromide, to give, respectively, thehydrochlo ride, 'hyd'robromide, sulfate (or bisulfate), phosphate (orTABLE 2 3,6-Ol-17-One Rotation Ultraviolet Spec- Example 16-Ary11deneSubstituent (yield) M.P. (corn) (recrystallization solvent) [04]., 1%trum Am. (6) I I in CHGla) 10 d-Methoxybenzylidene (85.0%) 218.4220.6(methanol) +45. 0 234 mp (8,700);

I 323 mp (28,100). 11; 2Pyridylmethylene (06.0%) 180.4182.4(acetonitrileLs; 57. 6 264 my (12,300);

1 V 272 m 13,000); r 209 mu (20,000). 12 4 Pyridylmethylene (93.0%)233.8237.0 (ethyl acetate) +10. 5 280-111 (24,300). l34-.Dimethylaminobenzylidene (73.5%)--. 250.4255.8 (methanol) +59. 7 252m (91200);

7 382111 1 32,700). 14 4-Benzyl0xybenzylidene (94.5%) 207.8209.4 (ethylacetate) +35. 6 233 m (9,200

acid phosphate), lactate, tartrate (or bitartrate), citrate (or acidcitrate), quinate, benzenesulfonate, methochloride, methobromide,rnethiodide, ethobromide, butobromide, allobromide, benzobromide,o-chlorobenzochloride, or 2-phenylethobromide salts ofl6-(4-dimethylaminobenzylidene)--androsten-35-ol-17-one.

16 (2-pyridylmethylene)androstan-3fi-ol-17-one (Example 11) and 16(4-pyridylmethylene)androstan-3flol-17-one (Example 12) were found tohave coronary dilator activities 178% and 224%, respectively, that ofpapaverine when injected into the isolated rabbit heart at a dose levelof 0.025 mg. per heart.

By causing androstan-3l3-ol-17-one to react with2-thiophenecarboxaldehyde, 3 thiophenecarboxaldehyde,2-furancarboxaldehyde, S-furancarboxaldehyde, 4-fluorobenzaldehyde,4-bromobenzaldehyde, 4-iodobenzaldehyde, 2,4,6-trichlorobenzaldehyde, or3-chloro-4-methoxybenzaldehyde, there can be obtained, respectively,16-(2-thienylmethylene)androstan-ZaB-ol 17 one, 16 (3-thienylmethylene)androstan-3fl-ol-17-one, 16-(2-furylmethylene) androstan-3/3-ol-17-one,16-(3-furylmethylene)androstan-3 8-ol-l7-one,

1 6-(4-fiuorobenzylidene) androstan-3/3-ol-17-one, 16-4-bromobenzylidene) androstan-3 ,8-01- 17-one, 16- (4-iodobenzylidene)androstan-3 [3-ol-17-one, 16 (2,4,6trichlorobenzylidene)androstan-3B-ol-l7-one, or 16(3-chloro-4-methoxybenzylidene)androstan-Bfi-ol- 17-one.

'16-(4-methoxybenzylidcne)androstan-3p-ol-17-one can be caused to reactwith acetic anhydride, propionic anhydride, caproyl chloride, succinicanhydride, fl-cyclopentylpropionyl chloride, benzoyl chloride,p-nitrobenzoyl chloride, 3,4,5-trimethoxybenzoy1 chloride, phenylacetylchloride, or cinnamoyl chloride, by heating in the presence of pyridine,to give, respectively, 3fl-acetoxy-16-(4-methoxybenzylidene)androstan-17-0ne, 3B propionoxy-16-(4-methoxybenzylidene)adrostan-17-one, 3 B caproyloxy-16-(4-methoxybenzylidene)androstan 17 one, 3,6-carboxypropionoxy)-16-(4methoxybenzylidene)androstan 17- one, 3 ,B- fl-cyclopentylpropionoxy-16- (4-methoxybenzylidene)androstan-17-cne, 3p benzoyloxy-16-(4methoxybenzylidene) androstan-17-one, 3,8 (p-nitrobenzoyloxy) 16(4-methoxybenzylidene)androstan-17-one, 3,8 3,4,5-trimethoxybenzoyloxy)-l6-(4 methoxybenzylidene)androstan-l7-one,3fl-phenylacetoxy-16-( 4 methoxybenzylidene)androstan 17 one, or 3/3cinnamoyloxy 16 (4- methoxybenzylidene) androstan-17-one.

16 (4 dimethylaminobenzylidene)androstan-3fl-ol- 17-one can be caused toreact with hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, lactic acid, tartaric acid, citric acid, quinic acid,benzenesulfonic acid, ethanesulfonic acid, methyl chloride, methylbromide, methyl iodide, ethyl bromide, butyl bromide, allyl bromide,benzyl bromide, o-chlorobenzyl chloride, or 2- phenylethyl bromide, togive, respectively, the hydrochloride, hydrobromide, sulfate (orbisulfate), phosphate (or acid phosphate), lactate, tartrate (orbitartrate), citrate (or acid citrate), quinate, benzenesulfonate,methochloride, methobromide, methiodide, ethobromide, butobromide,allobromide, benzobromide, o-chlorobenzochloride, or 2-phenylethobromidesalts of 16-(4-dimethylaminobenzylidene) androstan-3B-ol-17-one.

fication occurred, the solid was dissolved in 50 ml. of warm ethanol,and the solution diluted with 2 liters of cold water. The crudeprecipitated product was collected by filtration and was washed wellwith water. Triturataion of the damp filter cake with 125 ml. of 2 Nsodium hydroxide resulted in a deep yellow solution which was filteredto free it of a small amount of insoluble material. The filtrate wasdiluted with an equal volume of water and then made acidic by theaddition of dilute hydrochloric acid. The reprecipitated phenolicproduct Was again collected and washed with water. Recrystallizationfrom aqueous acetonitrile gave 11.05 g. of 16-(4-hydroxybenzylidene)-2-androsten-17-one, M.P. 226-242 C., amounting to a61.5% yield. A sample, prepared by recrystallization from methanol, hadM.P. 25 0.425 5 .8 C. (corn); [a] =|122.5. Ultraviolet spectrum: k 236nm (68,300) and A 328 mu (e28,000). In the infrared, a strong hydroxylband appeared at 3.04 11. and carbonyl absorption at 5.92 A smallunresolved plateau was observed in the region 6.03 to 6.11 due to theisolated double bond in the A ring.

Acetate derivative.-A solution of 2.0 g. (5.3 mmoles) of 16(4-hydroxybenzylidene)-2-androstcn-17-one in 10 ml. of pyridine and 5ml. of acetic anhydride was heated to 100 C. for 30 minutes and thenpoured into 900 ml. of cold water. The crude product was obtained inquantitative yield, M.P. 204208 C. One recrystallization from ethylacetate afforded 16-(4-acetoxybenzylidene)-2- 'androsten-17-one, M.P.205-2075 C., [a] =+88.9. In the ultraviolet, absorption was: A 224 m(e8,800) and )t 298 my. (e25,800). In the infrared, bands characteristicof phenyl acetates were observed at 5.67;]. and 8.35 4 and the Ccarbonyl absorption appeared at 5.84

EXAMPLE 16 1 6- (4-It1eth0xybenzylidene) -5-Andr0sten-3fi-0l-17-One Hemisuccz'nate A solution of 16-(4-methoxybenzylidene)-5-androsten- 33-ol-l7-one (Example 3) (12.2 g.) and succinic anhydride (6.0 g.) in 125ml. of pyridine was heated under reflux for three hours. After it hadcooled to room temperature the solution was poured into 2 liters of coldwater. After being collected and dried, the crude hemisuccinate wasrecrystallized five times from acetone to provide 6.75 g. of16-(4-methoxybenzylidine)-5-andr0sten-3fl-ol-17-one hemisuccinate havingthe M.P. 208.6- 210.0 C. (corr.), [a] =-4Z.3. The infrared andultraviolet spectra were in accord with the structure.

The di(hydroxyethyl)ammonium salt of 16-(4-metl1-oXy-benzylidene)-5-androsten-3;3-ol-17-one hemisuccinate had the M.P.142.s 14s.s 0. (corn), a 44.4

16 (2,4-dichlorobenzylidene)androstan-3B-o1-17 one 7 can be preparedfrom androstan-3fl-ol-17-one and 2,4 dichlorobenzaldehyde by the generalprocedure described hereinabove.

EXAMPLE 15 1 6 (4-H ydroxybenzy lidene) -2-A ndrosten-l 7-One whenrecrystallized from acetone.

EXAMPLE 17 1 6-(4-Meth0xybenzylidene) Andr0stane-3,1 7-DioneCyclohexanone (40 g.) and16-(4-methoxybenzylidene)androstan-3fl-ol-17-one (Example 10) (20.75 g)were dissolved in 400 ml. of toluene. The solution was stirredmechanically and heated to boiling, then 50 ml. of the solvent wasdistilled out to ensure dryness. A solution of 10.4 g. of aluminumisopropoxide was added as a solution in ml. of toluene. The reactionmixture was stirred and heated under reflux for two hours and thencooled to room temperature. Dilute sulfuric acid (100) ml. of 5%) wasadded, followed by 100 ml. of water. After the mixture had been stirredvigorously for a few minutes, the layers were separated and the organicphase was Washed with three 100 ml. portions of water. Steamdistillation of the toluene solution for two hours effected removal ofcyclohexylidene cyclohexanone and afforded a solid residue of crudediketone. Recrystallization from ethyl acetate gave three crops ofcrystals totalling 15.88 g., melting in the range 253272 C. Severaladditional recrystallizations from benzene gave 16- (4methoxybenzylidene) androstane 3,17 dione, M.P. 266.0-278.2 C; (corn),[u] =+21.9. In the infrared, very strong absorption was evident at 5851, resulting from overlapping absorption of the two carbonyl functions.

EXAMPLE 18 16-(4-methoxybenzylidene)-4-androstene 3,17 dione wasprepared from 20.3 g. of 16-(4-rnethoxybenzylidene)-androst-5-en-3fi-ol-l7 -one (Example 3) and 49 g. of cyclo- V areduction of 30 mm; Hg in blood pressure when administered orally torenal hypertensive rats at a dose level of 100 rug/kg.

7 EXAMPLE 19 1 6-(4-Pyridylmethylene)Androstane-3,17-Di0ne A solution of13.0 g. of chromium trioxide in 50 m1. of glacial acetic acid and 50 ml.of water was added during five minutes to a stirred and cooled solutionof 25.0 g.

of 16 (4-pyridylmethylene) androstan-3 /3- ol- 17-one (Example 12) in300 ml. of glacial'acetic acid. After the addition, the dark solutionwas stirred at room tempera-' ture for four hours. Methanol (25 ml.) wasadded, and the solution was poured intotwo liters of cold water.

the addition of excess 35% sodium hydroxide solution,

causing precipitation of the product as a gum which hardened on standingovernight. The crude product was collected and recrystallized from amixture of acetone and n-hexane to give two crops of crystals: 16.46g.,- M.P. 174176.5 C. (un corn) and 2.95 g., M.P. 170 174 C. (uncorn).

Two additional recrystallizations from the same solvent afiorded asample of 16-(4-pyridylmethylene)androstane- 3,l7dione which melted at176l77 C. (uncorrn), then resolidified and remelted at 196197 C.(uncorr.). Seeding experiments substantiated the supposition that thiswas a simple case of polymorphism; The rotation was [d] j =+8.8. Theultraviolet spectrum was identical with that of the starting material,and the infrared spectrum showed the disappearance of hydroxylabsorption and the appearance of a second carbonyl band at 5 .85 1.

20 I a) 1 6 ,6- (2 -Pyridy lmethyl Andr0stan-3 B-ol-J 7-0l1ev A solutionor. 20.0 g. of 16-(2-pyridylrnethylene)- androstan-3fl-ol-17-one(Example 1.1) in 600ml. of 95% The dark-colored aqueous mixture was madebasic by ethanol was hydrogenated in' the presence of 10 got palladiumhydroxide (30%, on" strontium carbonate). One molar equivalent ofhydrogen was absorbed within 20 minutes, after which the catalyst wasremoved by filtration and the filtrate evaporated to dryness underreduced pressure. Recrystallization of the crude, solid .residue fromethyl acetateafiorded 15.85 g. of product melting in the range 167 177C. (uncorn'). Chromato:

detected its ultraviolet absorption at 298 m .Elution graphicpurification on silica wasnecessary to separate 7 the product from 45%of starting material which was ofthe chromatogram with:5% acetone inether,followed.

' l0 the ultraviolet at M 258 rm. (5 3,400); A 262 mu (e 3,900) and i269 my 6 2,900).

16/3-(2 pyridylmethyDandrostan 3/3-ol-17-one was found to have acoronary dilator activity 77% that of papaverine when injected into the'isolated rabbit heart at a dose level of 0.025 mg. per heart.

' Methobromide A solution of 24.7 g. of 16B-(2-pyridylmethyl)androstan-3fl-ol-l7-one and 8.5 g. of methyl bromide in 400 ml.ol'benzene and 350 ml. of acetonitrile was heated to 100 C. for twohours in a' stainless steel autoclave.

After cooling to room temperature, the reaction mixture was distilled todryness under reduced pressure. The residual solid was triturated with750 ml. of boiling water plus several grams of activated carbon andfiltered. Three crops of colorless'crystals were obtained by successiveconcentration and cooling of the aqueous filtrate. The combined producttotalled 25.36 g., M.P. 249-254 C.(dec.) (uncorn). Successiverecrystallizations from water, ethanol and acetonitrile containing 5% ofwater gave pure 16B-(2-pyridylmethyl)androstan-3fi-ol-l7-one methobromide, M.P. 2480-2502 C. (corn), [a]

+83.6 (1% in water). The ultraviolet spectrum showed a single unresolvedpeak: A 270 m (e 7.000). In the infrared a broad strong band appeared at286 .44.10 and carbonyl absorption at 574 16- 2-thienylmethyl eneandrostan-3/3-ol- 17-one, 16- 2- furylmethylene)androstan-3l3-ol-17-one,16-(2,4-dichlorobenzylidcne)androstsin-3dol-l7-one, andl6-(4-din1ethylaminobenzylidene)androstan-3/3-ol-l7-one can be similarlyhydrogenated to give, respectively, .1 6,8-(2-thienylmethyl) androstan3,8-ol-l7-one, l6li-(2-turylmethyl)androstan- 35-01-1 7-one, 1 6p-2,4-dichlorobenzyl androstan-3 (3-01- 17-o'ne, and'16,6-(4-dimethylaminobenzyl)androstan-Sflo1-17-one.

EXAMPLE 21 reversal of diethylstilbestrol dipro'pionate effect onpitui,-j

.tary and adrenal weights in male rats at a dose level of 20 mg/kg. perday. V 1

EXAMPLE 22 v 3 ii /1 cel0xy-] 6 ,3- 4M etlzoxybenzyl )Androstan-Z 7-0ne"'A solution of 13.9 g. of16 (4-methoxybenzylidene) aandrostan-3fl-ol-l7-one (Example 10) in 15 ml. of acetic anhydride and40 ml. of pyridine was left atroom tern perature for 24 hours. Dilutionwith 600 ml. of cold water afforded, after filtration anddrying, aquantitative yield of 3 3-acetoxy-16-(4-methoxybenzylidene)androstanE 17 one, 15.4 g., M.P. 192.5.1 9 3 C. (uncorr.). A solution of 10.0 g.of-the forementioned acetate in 3 00 1311. of ethyl acetate'washydrogenated with the aid of 2.0 g. of palladium hydroxidelcatalyst (2%on strontium carbonate) at room temperature under a pressure I of 4atmospheres of hydrogen- Repeated recrystallization from ethanolprovided SB-acetoxy l6fi-(4amethoxybe'nzyl)androstan- 17-one, V -M.P.177;6-180.2 .0. (corn), [a] :-.+l9l.4. The ultraviolet and infraredspectra were consistent with the postulated structure; in the infraredavery strong 5.76

py id carbonyl band resulted from superimposition of acetate upon C-17carbonyl absorption.

EXAMPLE 23 3 fl-A cetoxy 6 ,8- 44M ethoxybenzyl Androstan-I 7-5-0l Asolution of 16.1 g. ofBfi-acetoxy-16fi-(4-methoxybenzyl)androstan-17-one in 1000 mi. ofmethanol and 500 ml. of tetrahydrofuran was stirred and cooled to 3 C.by means of an ice bath. Sodium borohydride (3.0 g.) dissolved in 30 ml.of cold water was then added, after which the ice bath was removed andthe solution was allowed to come to room temperature. After beingstirred for an hour, the solution was acidified by the addition of ml.of glacial acetic acid. The solution was distilled under reducedpressure until crystallization of the product began, after which it wascooled in ice. The product was collected by filtration, washed with coldmethanol, and dried, giving 14.45 g., M.P. 160.5162 C. A second cropfrom the filtrate weighed 0.95 g. and had M.P. 153-158 C. Tworecrystallizations from methanol afforded 3,8-acetoxy-16fi(4-methoxybenzyl)androstan- 17-5-01, M.P. 162.2163.6 C. (corn), [a]=|-27.9. The ultraviolet spectrum was identical with that of thestarting acetoxy ketone, and in the infrared there was hydroxylabsorption at 2.86

EXAMPLE 24 (a) 16,6-(4-Meth0xybenzyl)Androstane-3fi,17fi-Di0l To asolution of 40.0 g. of 16-(4-methoxybenzylidene) androstan-3fi-ol-l7-one(Example 10) in 600 ml. of tetrahydrofuran was added 4.0 g. of acatalyst composed of palladium hydroxide distributed on strontiumcarbonate. The mixture was agitated under four atmospheres of hydrogenpressure until absorption of gas had ceased. Since 1.65 molarequivalents of hydrogen had been taken up, it appeared that somereduction of the carbonyl group at 0-17 had occurred. A solution of thecrude hydrogenation product in one liter of methanol was stirred andcooled to 1 C. by means of an ice bath. A solution of 7.6 g. (200mmoles) of sodium borohydride in 75 ml. of cold water was added as aslow stream over a period of three minutes, during which time thetemperature of the reaction mixture rose to 9 C. and then began tosubside. The solution was then allowed to come to room temperature andwas stirred for an hour. Acidification was accomplished by the cautiousaddition of 25 ml. of glacial acetic acid, after which the clearsolution was concentrated to a volume of 500 ml. of distillation underreduced pressure. Cooling in ice gave colorless crystals which werecollected by suction filtration and Washed with cold methanol. Afterbeing dried, the product weighed 35.4 g., and melted at 90-100 C. withgas evolution. Dilution of the filtrate and washings with 2.5 liters ofcold water afforded 5.15 g. additional solid, M.P. 110115 C. A portionof the product was recrystallized from methanol; after fourrecrystallizations there was obtained a sharply melting compound (M.P.139.5440 C.) which however was still apparently solvated, judging by itsbehavior on melting. Only after prolonged drying over P 0 at 100 C. and1 mm. pressure was an apparently solvent-free sample of16,8-(4-methoxybenzyl)androstane-3fi,17fi-diol obtained, which had M.P.133.0-143.0 C. (corn), [oc] =|46.6. In the infrared there appeared astrong hydroxyl band at 2.94 1, plus aromatic absorption at 6.21 631 and6.61 ,u. 'The ultraviolet spectrum was characteristic of 4-alkylanisoles: A 278 m (6 1,800), A 285 m (6 1,500) and A 224m (6 10,500).

(b) 16 -(4-Metlz0xybenzyl)Andr0stan-3,BOl-17-One A ten gram portion ofthe crude hydrogenation product of 16-(4-methoxybenzylidene)androstan-3fi-ol-17-one was subjected to columnchromatography on silica. Elution with ether in n-pentane and repeatedrecrystallizationfrom aqueous methanol gave a sample of 16,8-(4-iethoxybenzyl)androstan-3l3-ol-17-one melting at 155- 162 C. (uncorn)which showed some signs of solvation despite careful drying. Therotation was [oc] +910".

Acetylation of a small portion with acetic anhydride and pyridine gave3/3-acetoxy-16fl-(4-methoxybenzyl) androstan-17-one, identical with thecompound prepared in Example 22.

(c) 3 8,] 7fi-Diacet0xy-1 6 ,8- (4-M ethoxybenzyl Androslane A solutionof 35.55 g. (86 mmoles) of16,8-(4-methoxybenzyl)androst'ane-3fi,17B-diol (part a) in 50 ml. ofpyridine and 50 ml. of acetic anhydride was heated to 100 C. for 30minutes and after cooling to room temperature was diluted with 2.5liters of cold water. The diacetate precipitated as a guru whichcrystallized. The slightly sticky solid was broken up, collected bysuction filtration, and washed well with water. Recrystallization of thedamp crude produce from methanol gave 31.0 g. of solid, M.P. -100 C.Recrystallization was best effected from a mixture of ethyl acetate andn-hexane. By exhaustive drying of recrystallized material in vacuo at 80C. for 24 hours solvent-free 313,1713-diacetoxy-16fl-(4-rnethoxybenzyl)androstane was obtained.

EXAMPLE 25 3,8,17/3-Diacet0xy-16/3-(4-Ox0cycl0hexylmethyl) A ndrostaneA. Birch reducti0n.-T0 a solution of 96.5 g. of 35,175- diacetoxy-16,B(4 methoxybenzyl)androstane (Example 24c) in a mixture of 1050 ml. ofanhydrous etherand 2750 ml. of freshly dried tetrahydrofuran was added8.5 liters of anhydrous liquid ammonia. The solution was stirredmechanically in a 22 liter flask fitted with a condenser cooled withsolid carbon dioxide, while 40 g. of lithium wire was added in shortpieces during 15 minutes. The blue-black solution was stirred forone-half hour after the lithium had been added. Absolute ethanol wasnext added in a slow stream from a dropping funnel at the maximum ratepermitted by flooding of the condenser due to the exothermic reaction.After 17 minutes the solution had become decolorized, by which time 500ml. of ethanol had been added. The condenser was removed and the ammoniawas evaporated by heating the vigorously stirred solution on a steambath. After the ammonia had been driven off, heat was applied morecautiously to evaporate the ether without heating the solution above 40C. The residual tetrahydrofuran solution was then diluted with 10 litersof cold water. An organic layer formed and was separated from theaqueous phase, and the latter was then extracted with three portions ofmethylene dichloride totalling 4500 ml. The solution formed by combiningthe extracts with the organic phase was dried over solid potassiumcarbonate for 30 hours.

B. Re-acetylatiom-After filtration to remove the drying agent, themethylene dichloride solution was distilled to dryness under reducedpressure. The residue was dissolved in 250 ml. of pyridine and 100 ml.of acetic anhydride. After 48 hours at room temperature, the solutionwas poured as a slow stream into six liters of cold water, and theproduct precipitated as a gummy mass from which the aqueous phase waseasily decanted. The gummy product was dissolved in acetone (800 ml.)and reprecipitated by dilution with water as before. The solid productwas collected by suction filtration and washed with water.

C. Hydr0lysis.--Without further purification, the crude dihydroenolether was dissolved in 1000 m1. of tetrahydrofuran and 1000 ml. ofmethanol, and a solution of 90 g. of oxalic acid dihydrate was added.The solution was left to stand for one hour at 30 C., and then wasdiluted with 3 liters of ether. The solution was washed with dilutesodium bicarbonate solution until it was free of acid, then twice with500 ml. portions of water, and finally with 500 ml. of saturated sodiumchloride. The combined aqueous washes were back-extractedcyclohexylmethyl)androstane, Ml. (corn), [a] ="+7.8. In theinfrared,.there appeared a sharp unbondcd'hydroxyl band at 2.87; and a.sharp,

, l3 with 500 ml. of ether, the extract-was washed inturn withbicarbonate, water, and sodium chloride and then combined with the mainether solution. The ether solution was dried overnight over anhydroussodium sulfate and distilled to dryness under reduced pressure.

D. Catalytic reduction-The oily unsaturated ketone was dissolved insufiicient ethyl; acetate to make 600 ml. of solution. Six" grams o f jpalladium on carbon was added, and the mixture was agitated at roomtemperature under a pressure of four atmospheres of hydrogen. Reductionproceeded'slowly and uptake of hydrogen ceased only after-agitation hadbeen conducted for hours. In that time, the solution had absorbed 99millimoles of hydrogenor 51% of theory, based upon the starting 16,8-(4-methoxyben2yl) compound. The hydrogenated mixture was filtered toremove the catalyst, which was Washed with several small portions ofethyl acetate. The combined filtrate and ,washingswere concentrated bydistillation under reduced pressure, affording 46.2 g. of crystalline3,8,17/3 diacetoxy 16,8 e (4-oxocyclohexylmethyl)- androstane, Ml 178182C. (uncorr.).- Evaporation of the filtrate gave an oily residue whichwas subjected to column chromatography on 750 g. of silica. Elution with20% ether in n-pentane gave 3.15 g. of 16fl-(4-methoxybenzyl) startingmaterial. Elution with 40% and 50% other in n-pentane gave the onlyother solidjobtained from the chromatogram, andatter onerecrystallization from n-hexane containing 10% acetone there was ob--istic of saturated six-membered ring ketones. The infrared spectrum wasentirely consistent with the structure depicted;-the major features werestrong ester carbonyl absorption at 5 .77,u. and a band at 5.82,u forthe saturated ketone.

EXAMPLE 2s 3 8,1 7 B-Diacctoxy-Z 6 ,8-(4 -0ximinocyc ohexylmethyl IAndrostane two hours. The solution was cooled to room temperature andpoured into 600 ml. of a mixture of ice and water. After onerhalf. hourat room temperature, the mixture was filtered, and the collected solidwas dried and recrystallized three times froma mixture of acetone andnrhexane to give 3,6,17fl-diacetoxy-16/3-(4-oximino- 186.6- 1878" C.

str'ongacetate-carbonyl band at 5 .78,u.. Other features in" i theinfrared were consistent with the oxime structure, including weakabsorption at 6.04;! for the C=N double bond. 1, j

EXAMPLE27 3,6,1 7 Diacet0xy-16fi- (4-Aza-5-Ox0cycl0heptyImethyl) vAndrostane A solution" of 5.0- g. of3,8,175-diacetoxy-16B-(4-oximinocyclohexylmethyl)androstane in 150 ml.of p-dioxane was heated to 50 C. 7 External. heating was discontinuedand the solution was stirredwhile 6.0 g. of thionyl chloride was addedin several small portions over a period of seven minutes. Thetemperature was maintained at 50-55 f C. by external heating for 15minutes, after which: the solution. was cooled to room. temperature;.Saturated aqueous. sodium bicarbonate solution (150 ml.) Was addedcautiously, and the resulting mixture was stirred vigorously-at roomtemperature for 15 minutes. The mixture was next diluted with 2 litersof cold water and left'to stand at room temperature for 12 hours. Theproduct was collected by filtration, washed with water and dried in air.The crude. amorphous product (5.2 g.) did not crystallize well, and wastherefore purified initially by column chromatography on Florisil(activated magnesium silicate). Elution of the column with increasingproportions of acetone in ether aiiorded only one solid product, whichwas eluted with 30% acetone in ether. Recrystallization fronra mixtureof acetone and n-hexane gave 3,8,'17fi-diacetoxy-16fi-(4-aza-S-oxocycloheptylmethyl)androstane, MP. 170;2174.2 C. (corn),

a EXAMPLE 2s 7 1 6B- (4-A ZucycloheptylmethyDAndrostan e-3,B,1 7 B-DiolA solution of 4.80 g. of 3,6,17,8-diacetoxy-16,8 (4-aza5-oxycycloheptylmethyl)androstane in 250 ml. of dry tetrahydrofuran wasadded in a slow stream at room temperature to a stirred mixture of 3.80g. of lithiumaluminum hydride in 250 ml. of tetrahydrofuran. The"mixture was stirred for one hour and then heated: under reflux foreight hours. Water. (7.6 ml.) was added drop- Wise to the cooledmixture, and stirring was continued for 15 minutes at room temperature.The reaction mixture, was filtered and the filter cake was Washed, withseveral small portions of tetrahydrofuran, whichwere combined with thefiltrate. Evaporation er the filtrate under reduced pressure afiorded. aclear semicry'stalline residue which was dissolved in 40 ml. of drymethanol.

The addition of 1.0 of .ethanolic hydrogen chloride solution (9.8 N)caused precipitation of the hydrochloride: 2.94 g., M.P. over 320 C. Asecond crop' of crystals mg.) was obtained from the filtrate. .Onerecrystallization of the combined material from a mixture of'methanol'and ethanol gave l6fi-(4-azacycloheptylmethyl)androstane-3fl,17fi-diolin the form of its hydrochloride salt hemihydrate, [a] 15.4 (0.5% inmethanol). The infrared spectrum was in agreement with the assignedstructure. Y

EXAMPLE 29 16 (1-MethyZ-Z-Piperidylmthfl) A ndr qstan- SB-Ol-J 7 0122 Asolution of 9.53 g. of 16B-(2-pyridylmethyl)androsta'n-3/3-ol-17-onemethobromide (Example 20, Part [2) in 300 ml. of 95% ethanol washydrogenated in the presence of 0.5 g. of platinum oxide catalyst. Afterthree moles of hydrogen had been absorbed, the catalyst was removed byfiltration and the filtrate concentrated to dryness. The residue wasdissolved in methanol, the solution cooled, a little isopropyl alcoholadded and the prodnot allowed to crystallize. The solid (4.31 g.) wascollected, recrystallized twice from ethanol, and dried at Y C. in vacuoover phosphorus pentoxide for twenty- 15 We claim: 1. A compoundselected from the group consisting of wherein R is a member of the groupconsisting of pyridyl, thienyl, fury], phenylvinyl and phenylsubstituted by from one to three substituents selected from the groupconsisting of halogen, di-lower-alkylamino, lower-alkoxy and benzyloxy;R is a member of the group consisting of hydrogen and Acyl; and X is amember of the group consisting of O, (H) (OH) and (H) (OAcyl); Acyl ineach instance being a carboxylic acid acyl group having from one to tencarbon atoms and a molecular weight less than 200; and acid-addition andquaternary ammonium salts of basic members thereof.

2. A compound of the formula C HR wherein R is phenyl substitued by fromone to three halogen atoms.

3. A compound of the formula 0 CH3 I CH-R wherein is pyridyl 4. Acompound of the formula 0 CH3 [I wherein R is phenyl substituted by fromone to three lower-alkoxy groups.

5. A compound of the formula 0 CH2 ll (Sim-H1 wherein Rt is a member ofthe group consisting of pyridyl, thienyl, furyl, l-lower-alkylpiperidyl,4-oxocyclohexyl, 4-oximinocyclohexyl, 4-azacycloheptyl,4-aza-5-oxocycloheptyl, and phenyl substituted by from one to threesubstituents selected from the group consisting of halogen,di-lower-alkylamino and lower-alkoxy; and X and X are members of thegroup consisting of O, (H)(OH) and (H) (OAcyl), Acyl being a carboxylicacyl group having from one to ten carbon atoms and a molecular weightless than about 200; and acid-addition and quaternary ammonium salts ofbasic members thereof.

14. A compound of the formula wherein R" is pyridyl,

15. 16/3- (4-methoxybenzyl) androstane-3fi,17B-diol.

16. 3 8,175 diacetoxy 16,6 (4 oxocyclohexyl- References Cited in thefile of this patent methynandrostane- UNITED TATES PATENTS 17. 313,175diactoxy 16,8 (4 aza 5 oxocyclo- S heptylmethyl)androstane 2,588,391Juhan et a1. Mar. 11, 1952 18. 16/3 (4 azacycloheptylmethyl)androstane 33, 5 OTHER REFERENCES 17fl-diol.

19. 165 (1 methyl 2 piperidylmethyl)androstang Chem" VOL April3,8-01-17-0ne.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF